Characterization of Non-Ischemic Dilated Cardiomyopathy in a Native Tanzanian Cohort: MOYO Study

Background: Non-ischemic dilated cardiomyopathy (NIDCM) is a common cause of heart failure with progressive tendency. The disease occurs in one in every 2,500 individuals in the developed world, with high morbidity and mortality. However, detailed data on the role of NIDCM in heart failure in Tanzania is lacking. Aim: To characterize NIDCM in a Tanzanian cohort with respect to demographics, clinical profile, imaging findings and management. Methods: Characterization of non-ischemic dilated cardioMyOpathY in a native Tanzanian cOhort (MOYO) is a prospective cohort study of NIDCM patients seen at the Jakaya Kikwete Cardiac Institute. Patients aged ≥18 years with a clinical diagnosis of heart failure, an ejection fraction of ≤45% on echocardiography and no evidence of ischemia were enrolled. Clinical data, echocardiography, electrocardiography (ECG), coronary angiography and stress ECG information were collected from February 2020 to March 2022. Results: Of 402 patients, n = 220 (54.7%) were males with a median (IQR) age of 55.0 (41.0, 66.0) years. Causes of NIDCM were presumably hypertensive n = 218 (54.2%), idiopathic n = 116 (28.9%), PPCM n = 45 (11.2%), alcoholic n = 10 (2.5%) and other causes n = 13 (3.2%). The most common presenting symptoms were dyspnea n = 342 (85.1%), with the majority of patients presenting with New York Heart Association (NYHA) Class III n = 195 (48.5%). The mean (SD) left ventricular ejection fraction (LVEF) was 29.4% (±7.7), and severe systolic dysfunction (LVEF <30%) was common n = 208 (51.7%). Compared with other forms of DCM, idiopathic DCM patients were significantly younger, had more advanced NYHA class (p < 0.001) and presented more often with left bundle branch block on ECG (p = 0.0042). There was suboptimal use of novel guidelines recommended medications ARNI n = 10 (2.5%) and SGLT2 2-inhibitors n = 2 (0.5%). Conclusions: In our Tanzanian cohort, the majority of patients with NIDCM have an identified underlying cause, and they present at late stages of the disease. Patients with idiopathic DCM are younger with more severe disease compared to other forms of NIDCM.


INTRODUCTION
Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by contractile dysfunction and left ventricular dilatation in the absence of significant coronary artery disease or valvular disease.Non-ischemic dilated cardiomyopathy is a common cause of heart failure with progressive tendency and poor outcome [1].It is reported to occur in one in 2,500 individuals in the general population of developed countries and has been shown to have high morbidity and mortality [2,3].Contrary to high-income countries where ischemic heart disease constitutes the major cause of cardiovascular mortality, in Africa, non-ischemic causes such as hypertension with its complications are currently the leading cause of heart failure [4,5].A systematic review involving sub-Saharan Africa (SSA) countries reports that hypertension is a key modifiable risk factor in heart failure in general as well as in cardiomyopathies [6].There is a higher prevalence of hypertension in SSA compared to high-income countries [5].
Non-ischemic dilated cardiomyopathy can be of primary origin (genetic, mixed, or predominantly familial non-genetic) or acquired or secondary (e.g., hypertensive, infiltrative or autoimmune) [7].Apart from genetic causes, there are other recognized specific forms of NIDCM, such as alcohol-induced, peripartum, and HIV-induced DCM, although some genetic mutations may influence their occurrence [8,9].Putting Tanzania into context, various studies have been conducted showing a tendency for a surge in ischemic cardiomyopathy, as seen elsewhere in the continent [4].Notwithstanding, various etiologies leading to NIDCM constitute major causes of cardiovascular morbidity and mortality [2].Although the Tanzania Heart Failure study (TaHeF) involving 427 patients did not report directly on NIDCM, it recorded only 9% of the study population in heart failure due to ischemic cardiomyopathy, suggesting that the majority fell into the non-ischemic category [10].A recent study done in Tanzania showed echocardiographic etiologies of heart failure (n = 459) were hypertension 40.1%, dilated cardiomyopathy 27%, rheumatic heart disease 23.2% and others 9.3% [11].
There is a dearth of information regarding the demographics, clinical profile, and imaging findings of NIDCM in the Tanzanian setup.The heterogeneous nature of the condition, with its diverse etiologies, calls for a detailed study of the Tanzanian cohort consisting mainly of black ethnicity to identify any peculiar characteristics.Currently, the available management guidelines for NIDCM are based on predominantly European white populations [12].
Characterization of non-ischemic dilated cardioMyOpathY in a native Tanzanian cOhort (MOYO), which literally translates to 'heart' in Swahili, aims to characterize NIDCM in terms of demographics, clinical profile, imaging as well and management offered in a Tanzanian cohort.This information may help in creating awareness and guidance in preventive measures as well as early detection of patients at risk to effectuate timely management.

STUDY DESIGN AND AREA
This is a prospective cohort study to characterize NIDCM at Jakaya Kikwete Cardiac Institute (JKCI).Jakaya Kikwete Cardiac Institute is the only tertiary-level hospital and the topmost referral hospital for cardiac diseases in Tanzania, which has a population of 64 million people, receiving cardiac patients from all regions of Tanzania.It has a bed capacity of 104 and around 1,600-2,000 outpatient weekly load.It also has an echocardiography laboratory that has seven ultrasound machines performing around 350 echocardiograms weekly.It also has two catheterization laboratories with 40 procedures per week, of which the majority are coronary angiography (n = 30) and percutaneous cardiac intervention (n = 10).

STUDY POPULATION, INCLUSION, AND EXCLUSION CRITERIA
All patients aged 18 and above with clinical diagnosis of heart failure and echocardiographic diagnosis of NIDCM with ejection fraction ≤45% at recruitment were enrolled.Exclusion criteria were signs of ischemic cardiomyopathy or valve disease on echocardiography, ECG, exercise stress testing or coronary angiography [13].Data was collected from echocardiography lab, catheterization lab, inpatient wards and outpatient clinics from February 2020 to March 2022.We had 409 eligible candidates for the study.However, three patients did not consent, and four patients did not have complete echocardiography reports; these seven patients were

Questionnaire
A structured questionnaire was used to record patients' socio-demographic and clinical data, including age, sex, hypertension and diabetes history, cigarette smoking and alcohol intake.Other information, including duration of heart failure symptoms, obstetric history, family history of similar illness, and sudden cardiac death, was collected.For each patient, a detailed history of the presenting symptoms was documented.
Dyspnea severity was used to grade patients into different classes of New York Heart Association (NYHA) classes I-IV according to their symptoms, depending on the degree of effort needed to elicit symptoms [12].Non-ischemic dilated cardiomyopathy, presumably due to Hypertension, was diagnosed as the end stage of hypertensive heart disease, usually the result of longstanding pressure overload, and consists of dilated cardiomyopathy with both diastolic dysfunction and reduced ejection fraction [14].Peripartum cardiomyopathy (PPCM) was defined as the onset of cardiomyopathy during the last month of pregnancy or within five months of delivery [15].Alcohol abuse was defined as the consumption of more than 14 units of alcohol in one week.Alcoholic cardiomyopathy was considered present when the cardiomyopathy was detected in an individual with a significant history of alcohol abuse in the absence of other known causes of myocardial disease [16].In this study, patients were grouped as DCM of other causes if they had underlying causes such as infection (e.g.HIV) or hormonal or drug-induced disease.Familial DCM was identified in patients with idiopathic DCM when two or more individuals in first-degree or second-degree relatives have/had DCM, or the presence of index patient with DCM and a firstdegree relative with autopsy-proven DCM or sudden death at ≤50 years of age [17].

Laboratory investigations
Routine laboratory test results of hemoglobin level and serum electrolytes were collected.According to the World Health Organization (WHO), anemia is defined as hemoglobin (Hb) levels <12.0 g/dL in women and <13.0 g/dL in men [18].Serum sodium is defined as normo-natremia (serum Na + 135 to 145 mEq/l, hyponatremia (serum Na + <135 mEq/l) and hypernatremia (serum Na + > 145 mEq/l).

ECG and exercise stress testing
A 12-lead resting electrocardiogram was obtained from all patients.A GEMAC2000 machine was used.An experienced cardiologist did the reading and interpretation of the ECG.Some patients underwent exercise stress testing using General Electric CASE V6.73 stress system applying the Bruce protocol; machine printouts were reviewed and confirmed by an experienced cardiologist [19].Ischemia was considered absent when there was no evidence of unequivocal pathological Q waves and/or ST-segment elevation or depression in serial recordings [20].

Cardiac imaging
Chest radiographs obtained from routine care were interpreted by the principal investigator, who is an experienced radiologist, noting the cardiothoracic ratio, cephalization and evidence of pulmonary edema and pleural effusion.Cardiomegaly in chest radiographs is considered present when the thoracic horizontal width of the heart divided by the widest internal diameter of the thorax (i.e. the cardio-thoracic ratio) is above 0.5 [21].
Echocardiography was performed on all patients, recording information on chamber sizes, ventricular systolic function, valvular regurgitation, presence of thrombi, regional myocardial function and pericardial effusion.Left ventricular ejection fraction (LVEF) was evaluated using the biplane method of disks (modified Simpson's) as per the American Society of Echocardiography and the European Association of Cardiovascular Imaging guidelines [22].Left ventricular systolic dysfunction was graded as mild (LVEF 41-51%) in males and (41-53%) in females, moderate (LVEF 30-40%), or severe dysfunction (LVEF <30%) [22].Visual assessment of the left ventricular ejection fraction was done as per the literature [23].Right

ETHICAL CONSIDERATIONS
This study was conducted in accordance with the Helsinki Declaration of Studies on Human Subjects.The study was approved by the Directorate of Research and Publications of MUHAS (P.MUHAS -REC-9-2019-060).Participation in the study was voluntary and all patients were educated about the importance of the study.Those who agreed had to sign informed consent forms before any data was collected.Patients who refrained from participation were assured of unbiased medical care.Patients' data were coded to ensure privacy and confidentiality.

DISCUSSION
Characterization of non-ischemic dilated cardioMyOpathY in a native Tanzanian cOhort is the first study performed in Tanzania to characterize patients with NIDCM specifically.The study was initiated to gain insights into the similarities and differences between different NIDCM cohorts regionally as well as globally.
The median age of our cohort is lower compared to published data from the PARADIGM-HF trial.However, in the PARADIGM-HF trial, age was recorded according to the investigator-reported cause of heart failure, where mean ages for hypertensive, idiopathic and other causes of heart failure were 64.7, 60.0 and 58.3 years, respectively.Conversely, males' predominance is more pronounced in PARADIGM-HF than in our cohort, while interestingly, non-ischemic idiopathic patients in PARADIGM-HF were more frequently female and Asian [25].
Our series contrasts with registries in Europe, where most patients have a higher level of education and robust health insurance, which potentially translates into a better understanding of their condition and compliance with management [26].However, our findings are similar to the INTERnational Congestive Heart Failure (INTER CHF) study which enrolled patients with heart failures in 16 countries, among which 1294 patients were from Africa.African participants were younger, had lower literacy levels, and were less likely to have health insurance [27].

CARDIOVASCULAR RISK FACTORS IN PATIENTS WITH NIDCM
Non-ischemic dilated cardiomyopathy, presumably due to hypertension in our cohort, is generally higher than observed in the PARADIGM-HF trial.The trial involved patients from Europe, Asia and Latin America; hypertensive etiology was most common in Latin America (21% of all cases) and least common in the Asia-Pacific [25].The difference may thus be explained by ethnicity since black ethnicity, predominant in our cohort, is an important risk factor for hypertension [28].Also, other factors need to be considered in explaining this phenomenon, such as the lack of hypertension screening programs in Tanzania.
Our study recorded comparable findings to a study in Sudan, where alcohol abuse was seen in 14.6% of the patients with DCM [29].A case-control study to compare the prevalence of nine genes associated with inherited DCM noted that DCM-causing genes were more prevalent in patients with alcoholic cardiomyopathy than in control subjects [30].remodeling in patients with NIDCM (n = 529).It recorded a difference in the degree of LV cavity dilatation associated with change in stroke volume; when compared to normal hearts [increase in end-diastolic volume of 0.7 mL per unit of rising BMI (mL/kg/m 2 )], there was a threefold greater LV cavity dilatation in NIDCM (+2.2 mL/kg/m 2 ) [31].Almost a quarter of participants in our series were obese, increasing their chances of developing LV remodeling as a complication, which may be compounded by other existing risk factors leading to NIDCM.
Hyperglycemia seen in patients with diabetes mellitus type 2 (T2DM) has been associated with cardiovascular alterations such as endothelial dysfunction, adverse effects of circulating free fatty acids (FFA) and increased systemic inflammation [32].Another study which compared NIDCM (T2DM-) and NIDCM (T2DM+) patients reported increased LV end-diastolic and endsystolic volume index and decreased LV ejection fraction.LV global strains progressively declined from the normal controls to the NIDCM (T2DM-) group to the NIDCM (T2DM+) group (all p < 0.017).In that study, NIDCM patients with T2DM showed an association between HbA1c and reduced LV myocardial strain on Cardiac MRI [33].In our series, we had some cases of T2DM; we need further studies with a larger sample to elucidate the role of hyperglycemia in NIDCM in Tanzania.
Cigarette smoking increases inflammation and triggers fibrotic processes, including cardiac fibrosis; this has a strong correlation with systolic dysfunction, diastolic dysfunction and abnormal electrical excitation [34].A study done in South Korea involving NIDCM patients using Cardiac MRI concluded that smokers had higher fatal ventricular arrhythmic events and poorer outcomes compared to non-smokers [34].There is a possibility that most patients in our study did not report smoking.However, they could be consuming other forms of tobacco, such as snuff, which may be detrimental to the cardiovascular system.

IDIOPATHIC DCM
The age of disease manifestation in our series concurs with current literature; it has been proven that most cases of Idiopathic DCM have a genetic origin.A meta-analysis involving 8,097 patients with idiopathic DCM in 40 studies showed that the average frequency of mutations in the investigated genes was between 1 and 5%.The mean age of idiopathic DCM onset was the beginning of the fifth decade for all genes [35].This finding brings attention to the importance of genetic screening in this subgroup in the current era of precision medicine.
Similar to our series, Bailly et al. analyzed 50 pedigrees with idiopathic DCM and found that 14 (28%) exhibited signs indicative of familial DCM dilated cardiomyopathy [36].Idiopathic DCM typically has a protracted asymptomatic phase, so its true frequency of familial tendency can only be fully understood through comprehensive family screenings.A subset of the MOYO cohort was subjected to a family screening (n = 120); it was revealed that 17 individuals (14.7%) had familial disease [37].This observation underscores the importance of implementing routine family screening to comprehend the extent of the problem.

PERIPARTUM DILATED CARDIOMYOPATHY (PPCM)
The proportion of patients with PPCM in our study is comparable to other studies in Africa.A Nigerian study showed that PPCM was the predominant form of cardiomyopathy in females found in 31.4% [38].Conversely, the proportion of PCCM in our study is high when compared to other regions, such as Europe.A retrospective study done in Denmark recorded an incidence of one in 10,149 deliveries [39].These findings call for better management of peripartum health in African women, as it has been noted that Black women are at higher risk of developing PPCM [40].

NIDCM OF OTHER CAUSES
Some of our patients presented with underlying viral infections such as HIV; the number of patients with HIV-induced cardiomyopathy seems smaller in this era where patients are on highly active antiretroviral therapy (HAART) regimens compared to pre-HAART era [41].Pathogenesis of NIDCM in patients with viral infection is explained by different etiological triggers confluence into a common autoimmune process leading to chronic inflammation, tissue remodeling and fibrosis [41].Global Heart DOI: 10.5334/gh.1298

CLINICAL SYMPTOMS AND DISEASE SEVERITY
Our findings differ from the European population; palpitations were only recorded in 36% of cases, and most patients presented with NYHA II at 42.7%, while in our series, the majority presented with more clinically advanced disease [42].The disparity among these cohorts can be explained by better awareness and access to care in European countries and existing screening programs.

ECHOCARDIOGRAPHIC AND CHEST RADIOGRAPHY FINDINGS
The majority of our patients presented with low LVEF, which implies severe systolic dysfunction and mitral valve regurgitation, which may be explained by an advanced state of the disease.A multi-centric international study observed that LVEF was an independent predictor of all-cause mortality [43].
Increased cardiothoracic ratio (CTR) in most patients in this cohort is consistent with a study done in South Africa, whereby increased CTR was seen in patients with DCM.Radiographic findings were confirmed by echocardiography as increased LV end-diastolic diameter [44].Pulmonary edema seen in our patients is comparable to other studies in Africa [29].

MANAGEMENT OF PATIENTS WITH DCM
Recently published data from the European Registry of Cardiomyopathy and Myocarditis (EORP) identifies beta-blockers as the pillar of management, as seen prescribed in 90% of their cases, followed by ACEIs or ARBs at 89% [42].These findings contrast with our setting, where diuretics were the most commonly prescribed due to advanced disease; however, there is a remarkable use of beta-blockers and limited use of ARNI and SGLT2 inhibitors.The unavailability of medication, financial constraints for most cases and lack of insurance coverage for novel drugs may explain the limited use.

LIMITATIONS/MITIGATION
In this study, a number of challenges were observed, including limited coverage of medical insurance and limited numbers of diagnostic facilities with high patient load.These limitations led to challenges in the investigations of patients as per internationally established protocols.Echocardiography was used as the main diagnostic tool for most patients.A significant number of patients lacked routine laboratory tests in their records.However, JKCI is the only specialized institute in the country; the data in this study provides insight into the Tanzanian population as far as NIDCM diagnosis and care status, thus guiding us into a better understanding of the condition as well as establishing appropriate management guidelines.

CONCLUSION
The MOYO study has demonstrated the feasibility of prospective characterization of a subset of patients with heart failure due to NIDCM in Tanzania.The findings of this study may enlighten health policies in forming tailored cardiovascular care for such a complex cohort.Notably, it has been found that patients with idiopathic DCM were often young, more often male, with no formal to a low level of education when compared to the main international registries.While most cases were due to idiopathic or presumed hypertensive cardiomyopathy, more than one in every ten patients had PPCM.Furthermore, at least half of the patients presented with severe heart failure, with the majority in NHYA functional class III-IV and LVEF <30, yet guidelinedirected medical therapy was suboptimal.These findings are a call to action, especially the need for an earlier diagnosis and strategies to facilitate evidence-based, proven treatments.
study byRayner et al. reporteda relationship between increasing BMI and left ventricular (LV) A